Physiol Rev 90: 983–1012, 2010;
doi:10.1152/physrev.00026.2009.
Mechanisms of Sound Localization in Mammals
BENEDIKT GROTHE, MICHAEL PECKA, AND DAVID McALPINE
Division of Neurobiology, Department of Biology II, Ludwig-Maximilians-Universitaet, Munich, Germany;
and UCL Ear Institute, University College London, United Kingdom
I. Introduction
II. Acoustic Cues for Sound Localization in Mammals
A. Cues for sound localization
B. Human sound localization: resolutions and limits
III. Neuronal Mechanisms for Spatial Processing in the Mammalian Auditory System
A. The neuronal basis for spectral integration: the basis for sound localization in the vertical plane
B. The binaural system: the basis for sound localization in the horizontal plane
C. Neuronal representation of auditory space
IV. Conclusions and Open Questions
Appendix A: Do Humans Lack the MNTB?
Appendix B: ITD Processing: Important Definitions
Appendix C: Role of Glycinergic Inhibition in ITD Processing in the MSO
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Grothe B, Pecka M, McAlpine D. Mechanisms of Sound Localization in Mammals. Physiol Rev 90: 983–1012, 2010;
doi:10.1152/physrev.00026.2009.—The ability to determine the location of a sound source is fundamental to hearing.
However, auditory space is not represented in any systematic manner on the basilar membrane of the cochlea, the
sensory surface of the receptor organ for hearing. Understanding the means by which sensitivity to spatial cues is
computed in central neurons can therefore contribute to our understanding of the basic nature of complex neural
representations. We review recent evidence concerning the nature of the neural representation of auditory space in
the mammalian brain and elaborate on recent advances in the understanding of mammalian subcortical processing
of auditory spatial cues that challenge the “textbook” version of sound localization, in particular brain mechanisms
contributing to binaural hearing.
I. INTRODUCTION
The ability to locate the source of a sound is critical
to the survival of a wide range of species. From their
appearance as primarily nocturnal animals more than 200
million years ago, mammals relied heavily on sound localization abilities to achieve this, and to this day, locating
the source of a sound remains an important sensory ability for prey and predator alike. Spatial hearing also contributes to human communication, for example, by providing cues as to the relative number and location of
sources and objects in the environment, helping determine the dimensions and characteristics of rooms and
enclosed spaces, and contributing to the “cocktail party
effect,” whereby listeners are able to hear out speakers
against other, interfering, voices in crowded listening environments1 (14).
In terms of its neural processing, sound localization
is highly complex but, nevertheless, represents a well1
In concert with other cues, mainly the spectrum of a voice.
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established model by which the principles of neuronal
computation might be explored. Here, we review recent
evidence concerning the nature of the neural representation of auditory space in the mammalian brain, concentrating on subcortical structures generally considered to
be specialized for processing auditory spatial cues, and
elaborating on recent advances in the understanding of
the mammalian auditory system that challenge the “textbook” version of sound localization, particularly brain
mechanisms contributing to binaural hearing. We focus
on several advances that have altered our understanding
of how sound localization is achieved in mammals.
1) The neural representation of auditory space is
apparently not confined to the form of a topographic map
generated by a labeled line system, the so-called “spacemap”; rather, source location appears to be represented
by a population of relatively broadly tuned spatial channels in both brain hemispheres.
2) While coincidence detection of binaural inputs in the
submillisecond range remains a basic feature of sound localization mechanisms, the historic view that neural tuning
0031-9333/10 Copyright © 2010 the American Physiological Society
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for preferred spatial locations based on interaural time differences (ITD) arises by means of purely excitatory axonal
“delay lines” does not appear to hold in mammals.
3) The binaural auditory system in mammals is less “hardwired” than has been imagined and appears instead to be highly
dynamic, able to adjust rapidly its tuning properties to take
account of the context in which sounds are heard.
Sound waves impinging on the ear result in a single,
one-dimensional movement of the tympanum (eardrum),
irrespective of whether the sound is a simple sinusoidal
wave emitted from a tuning fork, a mixture of temporally
and harmonically related sounds produced by a jazz combo,
or a complex muddle of voices at a cocktail party (Fig. 1). By
analyzing and comparing the one-dimensional movements
of the two eardrums, the auditory brain extracts the relevant
physical cues in what we perceive as auditory space, synthesizing auditory objects embedded in that space (Fig. 1).
Unlike the visual (retinotopy) and somatosensory (the sensory “homunculus”) systems, this analysis of auditory space
is achieved without recourse to any explicit representation
of auditory space on the receptor surface; rather, the sensory epithelium of the inner ear, of hair cells arranged along
the length of the basilar membrane, are systematically ordered according to the frequency of a sound (tonotopy)
rather than its spatial location or, indeed, any further specific
features of an object. For that reason, the representation of
auditory space is, to a large degree, computed in the central
auditory system by converging inputs from the two ears, inputs
that of themselves contain no explicit spatial information, onto
single neurons that lie deep within the brain stem. The specialized cellular properties and microcircuits of the lower auditory
pathways permit a detailed and high-resolution analysis of the
physical sound parameters, including temporal features that lie
in the submillisecond range.
Sound localization in mammals is based on two very
different means of analyzing the acoustic waveform (15).
The first constitutes a spectral analysis in which the comparison of sound energy across different frequency bands
arriving at each ear provides for sound-localization abilities
in the vertical dimension (including distinctions between
sources to the front from those behind; Fig. 2A). Although
better performance based on frequency spectra may be possible using both ears, it represents an essentially monaural
cue for sound localization, generated largely by the direction-specific attenuation of particular frequencies by the
pinna and concha of the outer ear. The second means by
which sound localization is achieved is based on detecting
and comparing differences in the movement of the two
eardrums. This binaural computation, which takes place
mainly within narrowband sound-frequency channels, underlies sound localization in the horizontal dimension. Two
interaural differences are available to such binaural analysis.
FIG. 1. Auditory scene analysis. The temporal and harmonical interplay between multiple instruments, for instance, in a jazz tune, results in
a complex composite waveform. When impinging on the ears, this waveform generates a one-dimensional movement of the eardrums. The auditory
system is able to extract all relevant physical cues to identify and distinguish the various sound sources, i.e., the instruments, from this
one-dimensional movement of the eardrums.
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
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FIG. 2. Cues for sound localization. A: spectral analysis as a monaural cue for sound localization in the vertical plane. Interaction of a broadband
sound with the head and, primarily, the outer ear alters the effective spectrum of the sound impinging on the eardrum in a manner dependent on
the location of the sound source in the vertical plane. Most prominently, the central notch (black arrows) in the effective spectrum of the sound
shifts to higher frequencies when the sound source is shifted from below (⫺45°, green) to above the horizon (⫹45°, red). The spectra shown are
digitally computed from 1-s white noise stimuli (cutoff frequency, 44.1 kHz) convoluted with KEMAR head-related impulse responses and averaged
over 50 repetitions. B: interaural time differences (ITD): the difference in the arrival time (⌬t) of a sound wave (gray lines) at the two ears is used
to localize a sound source in the horizontal plane. For frequencies below ⬃2 kHz, information in the fine structure of the sounds is available for ITD
processing. C: interaural level differences (ILD): for frequencies higher than ⬃2 kHz, the shadowing effect of the head creates increasingly sizable
differences in the intensity of the sounds at the two ears (⌬I) that are utilized for sound localization in the horizontal plane.
First, sounds not arising directly from in front (or behind)
arrive earlier at one ear than at the other, creating an ITD
(Fig. 2B). Second, for wavelengths roughly equal to, or
shorter than, the diameter of the head, a shadowing effect is
produced at the ear further from the source, creating an
interaural intensity, or level, difference (IID or ILD, respectively) (Fig. 2C; Refs. 192, 245).
It is important to note at this juncture that other
nonmammalian vertebrates, and some insects, have
evolved different solutions to the problem of sound localization. Some fish, for example, exploit particle motion
caused by near-field sound stimulation directly exciting
hair cells in the inner ear which are oriented parallel to
the motion of the water particles. As different hair cells
are oriented in different directions, the excitation pattern
of the population of hair cells allows the fish to locate
sound sources (reviewed in Ref. 52). Certain flies possess
hearing organs located at the center of the frontal thorax
that, by mechanical means, enhance minute ITDs by several orders of magnitude, rendering them amenable to
neuronal processing (140; reviewed in Ref. 200). A further
example is the frog ear, which effectively operates as a
pressure difference receiver: sound impinges on the frog’s
tympanic ears not only directly from outside, but also
indirectly through the mouth and, via the open Eustachian
tubes, from the opposite ear (54 –56, 196, 197). As a consequence, the relatively small differences in distance traveled by the sound to the inner and outer sides of the
eardrum generate location-dependent interference patterns in the movement of the tympanum, ultimately creating directional sensitivity at the level of the receptor
organ (56). Reptiles and birds use similar means of “widPhysiol Rev • VOL
ening” their effective interaural distance by acoustically
(mechanically) coupling the tympani via a rigid tube that
connects the middle-ear cavities (reviewed in Ref. 35).
Accordingly, reptiles and birds experience larger ITDs
than do mammals with equivalent head sizes (97, 205).
In this context, it is important to note that, within the
group of tetrapods, tympanic ears evolved independently
in frogs and mammals, and likely two or even three times
in “reptiles” (Fig. 3). Birds inherited tympanic ears from
their archosaur ancestors.2 Interestingly, the parallel evolution of tympanic ears in these groups occurred roughly
around the same time, during the Triassic (⬃210 million
years), more than 100 million years after the lineage that
eventually produced mammals split from the lineages
from which frogs and “reptiles” evolved (4, 36, 37). To this
end, since no common ancestors of these groups existed
capable of detecting air-borne sounds, mechanisms for
sound localization necessarily evolved independent in
these different groups of tetrapods. This offers a cautionary tale: although much may be learned from comparative
investigation of sound localization in birds and frogs (as
well as crickets, grasshoppers, and other animal models
that have significantly advanced our understanding of
auditory processing), the very fact that brain mechanisms
for sound localization evolved independently across these
different groups means that principles of neural processing
underpinning localization abilities in one species do not
necessarily explain how this task is achieved in another. To
2
Archosaurs: crocodiles, pterosaurs, dinosaurs, and their descendants, the birds.
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FIG. 3. Independent evolution of tympanic ears in vertebrates. The appearance of tympanic ears (indicated by black closed circles/oval) in the
mammalian lineage (blue) occurred roughly around the same time as in frogs (“Anura,” green), “reptiles” (yellow), and the avian ancestors
(“Archosaurs,” orange/red) in the Triassic ⬃210 –230 million years ago. Importantly, no common ancestor existed that had developed tympanic ears;
hence, the evolution of tympanic ears occurred independently for these groups.
this end, the elegant “textbook” understanding of auditory
spatial processing, based, as it is, largely on findings in birds,
cannot per se be assumed to explain the function of the
mammalian brain with respect to sound localization (76).
Below, we discuss three recent shifts in our understanding of spatial hearing in mammals, reserving discussion of other animal groups, including birds, for comparative purposes only.
II. ACOUSTIC CUES FOR SOUND
LOCALIZATION IN MAMMALS
A. Cues for Sound Localization
Many mammals, including humans, make use of the
two binaural cues, ITD and ILD, to perform sound localization with an accuracy of just a few degrees (15, 19). Brain
mechanisms underpinning such accuracy have been the subject of investigation since at least the middle of the 19th
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century. At that time it was understood that ILDs constituted
potential cues for locating the source of a sound, but it was
equally well recognized that these cues become vanishingly
small as the frequency of sound is reduced, i.e., as the
wavelength increases relative to the size of the head. Whilst
the possibility that ITDs also constitute a potential cue was
recognized, it was widely considered that such tiny differences, limited as they are to the submillisecond range, lay
beyond the resolving power of the human brain. To this end,
Rayleigh’s (1907, Ref. 192) confirmation of Thompson’s
(1882, Ref. 245) earlier work demonstrating that interaural
phase differences (IPDs) of low-frequency signals were indeed detectable by human listeners led to formalization of the
duplex theory of sound localization; ILDs were employed in
high-frequency localization tasks and timing differences (IPDs
or ITDs) for localization of low-frequency sounds.3
3
Note that this does not hold for near-field sounds; low-frequency sounds
also produce significant ILDs for distances roughly within arm range (217).
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
In addition to binaural cues, the auditory system
exploits frequency-specific modifications in the magnitude and phase of the sound reaching the eardrum that
arise from the interaction of the sound with the head and
the ears, to determine source location in the vertical
plane. These spectral cues for localization underpin the
ability to disambiguate the so-called cone of confusion,
resolving sources in front from those behind as well as
determining their elevation, a task not possible using
binaural cues alone (15). The function describing these
spectral modifications, which are generated largely by the
pinna and concha of the outer ear, is referred to as the
head-related transfer function, or HRTF (colored traces in
Fig. 2A). Spectral cues for localization consist of notches
(or changes) in the sound spectrum at specific frequencies; the exact frequency and magnitude of the notch
changing as the location of the source shifts in elevation
(19). Spectral cues can be manipulated by modifications
to the external ear, and the extent to which birds and
mammals, including humans, can adapt to the altered
cues that arise from these manipulations demonstrates
their importance in localization tasks. For example, immediately following insertion of ear molds that permit the
passage of sound to the tympanic membrane, but alter the
shape of the concha, human listeners’ performance is
degraded to the extent that they have trouble distinguishing the location of sounds in the vertical plane (although
left-right discriminations appear unaltered). Over the
course of several weeks, however, performance improves
such that by the end of ⬃1 mo, listeners have adapted
almost completely to the altered cues. Interestingly, subsequent removal of the ear molds leaves no residual deficit in performance, suggesting that sensitivity to spectral
cues represents a learned behavior (96). This is perhaps
not surprising given the multitude of complex sounds that
might arrive from many different directions, with various
features of the source, the environment, and the head
itself all contributing to the final sound impinging on the
tympanum.
B. Human Sound Localization: Resolutions
and Limits
Humans show remarkable abilities in sound localization, discriminating changes of just 1–2 degrees in
the angular location of a sound source (13, 118). Studies under listening conditions using headphones (which
enables the isolation of specific cues) confirm the remarkable accuracy of human spatial hearing, with
thresholds as low as 10 ␮s for ITDs (119) or 1–2 decibels for ILDs for presentations of binaural clicks (254).
For the ITD cue at least, this represents a level of
resolution that must be considered with respect to the
millisecond duration of nerve action potentials transPhysiol Rev • VOL
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mitting information in the brain. Threshold sensitivity
to ILD, whilst impressive, is no better than sensitivity to
sound level per se (151).
Rayleigh’s classical distinction of the duplex theory (1907, Ref. 192), separating cues for auditory spatial
processing into low- and high-frequency processes, was
seemingly confirmed by Stevens’ and Newman’s (1934,
Ref. 233) investigations of absolute localization performance in humans, in which blindfolded listeners were
required to indicate the location of a speaker delivering
pure tones of various frequencies. Discounting sources
to the front and back, where ITD information is ambiguous, performance was best for frequencies below ⬃2
kHz, and above 5 kHz, with intermediate frequencies
eliciting the highest number of localization errors, suggesting an incomplete representation of either cue over
this range.
Psychophysical studies using headphone stimulation
have sought to determine the range of ITD detectors
represented in the human brain. Based on measurement
of ITD discrimination thresholds and binaural unmasking,
the range of ITDs encoded is considered to be 1) roughly
constant across the range of sound frequencies at which
sensitivity to ITDs in the fine-structure of sounds is observed (⬍1,500 Hz) and 2) set largely by the physiological
range (⫾700 ␮s in humans) but with ITDs up to at least
⫾3,000 ␮s explicitly encoded in each sound-frequency
band (251). ITDs longer than the physiological range can
be experienced over stereo headphones, arising naturally
when multiple sound sources interact, and when acoustic
reflections are present (although at high fluctuation rates;
compare Ref. 150).
III. NEURONAL MECHANISMS FOR SPATIAL
PROCESSING IN THE MAMMALIAN
AUDITORY SYSTEM
Mechanical deflections of the eardrum in response to
sound stimulation are transmitted to the cochlea via the
three middle ear bones, the ossicles, which act as an
impedance-matching device effectively coupling air-borne
sound to the fluids of the inner ear. Hair cells in the organ
of Corti, the sensory epithelium that runs the length of the
basilar membrane of the cochlea, transduce mechanical
energy into bioelectric activity, and this activity, in the
form of nerve action potentials, is transmitted via the
auditory nerve to the central auditory nervous system
(Fig. 4). The central auditory nervous system can be
considered as consisting of different ascending streams,
or functionally segregated pathways. For instance, three
distinct pathways project from different subdivisions of
the cochlear nucleus, the first synaptic station in the
auditory brain stem (206). The subdivisions that make up
the cochlear nucleus comprise several neural subtypes
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GROTHE, PECKA, AND McALPINE
FIG. 4. The mammalian ascending auditory pathway. Simplified circuit diagram of ascending pathways involved in sound localization. See text
for details.
with very different temporal discharge patterns (166, 198).
Bushy cells in the ventral cochlear nucleus, for instance,
represent a critical stage in the binaural pathway, responding faithfully to the temporal structure of sounds,
either by phase-locking to the fine structure of sounds (up
to ⬃3 kHz) or to the envelope of high-frequency sounds.
In fact, due to a process of monaural coincidence detection, their responses appear even more temporally precise
than those of their auditory nerve inputs (106). Bushy
cells target the principal nuclei of the superior olivary
complex (SOC) (135, 235, 257; review in Ref. 209), where
the binaural comparisons that underlie ILD and ITD processing occur (68). The SOC outputs target the dorsal
nucleus of the lateral lemniscus and the inferior colliculus
(IC) (1, 22; review in Ref. 79). In contrast to the binaural
pathways, monaural pathways originate from cell types in
the ventral and dorsal cochlear nucleus, largely targeting
the lateral lemniscus or, via a direct pathway that bypasses the remaining brain stem nuclei, the IC on the
opposite side of the brain (209). The IC itself represents
an obligatory synaptic station for almost all ascending
pathways. It is characterized by a high degree of convergence and by rather complex response properties, at least
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compared with those found at lower auditory stations. It
would appear that at the level of the IC, all acoustic cues
have been processed and filtered into separate streams,
forming a basis for object recognition, which can be
attributed to the next synaptic levels in the thalamocortical system (Fig. 4). In this review we concentrate largely
on those pathways and nuclei up to the level of the IC,
whilst higher processing is not considered.
A. The Neuronal Basis for Spectral Integration:
the Basis for Sound Localization in the
Vertical Plane
A significant amount of literature exists detailing the
responses of neurons in the dorsal division of the cochlear nucleus (DCN). DCN neurons appear particularly
specialized for processing spectral cues, whilst more recent investigations have begun to examine neural coding
of spectral cues for localization in the IC, including how
coding of spectral cues is modified between the lower brain
stem and the IC. Responses of the so-called “type IV” neurons of the DCN appear to be determined by a dedicated
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
neural circuit within the DCN itself (167) (Fig. 5A1). Type IV
neurons show a small “island” of near-threshold activation around their characteristic frequency (CF; the frequency at which threshold for tone-evoked responses is
lowest), with a larger central inhibitory area (CIA) at
higher sound intensities (49, 99) (Fig. 5B, left column).
The CIA can provide for inhibition more broadly tuned than
the excitatory response area of type IV neurons through
convergent input from multiple (differently tuned) type II
DCN neurons (e.g., Ref. 229). The convergence of excitatory
inputs from primary auditory nerve fibers (ANFs) and inhibition derived from type II DCN neurons (themselves also
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thought to be the target of Onset-C inhibition; Ref. 85),
renders type IV neurons particularly sensitive to (inhibited by) notches in the acoustic spectrum, presumably
those generated by the interaction of sound with the head
and pinna (99, 276). How might such neurons encode the
potential cues for sound-source elevation such notches
provide? The answer lies in understanding the output
neurons to which type IV neurons project. Neurons in the
IC described as “type O,” they possess a circumscribed
frequency-versus-intensity response area, are the main
target of DCN type IV neurons (49) (Fig. 5A2). When
stimulated with pure tones, type O neurons, like type IV
neurons, show a largely inhibitory receptive field, with a
small “island” of excitation at low stimulus intensities.
However, when stimulated with broadband sounds containing a spectral notch, mimicking the effect of the directionally dependent HRTF, they respond with essentially the opposite characteristics to type IV neurons in
the DCN, showing considerable excitatory responses for a
single notch frequency, particularly at higher sound intensities, flanked by inhibitory regions generated by all other
notch frequencies (49, 189) (Fig. 5B, right column). Thus
IC neurons appear to show an essentially unambiguous
response to the frequency of a spectral notch. It has been
argued (49) that the pathway from type IV neurons in the
DCN to type O neurons in the IC is uniquely specialized
for processing directionally dependent spectral features
generated by the HRTF. Furthermore, modifications in
the processing of spectral cues between DCN and IC,
specifically the inversion of excitatory and inhibitory responses, is likely provided for by convergent GABAergic
inhibition at the level of IC (48) (Fig. 5A2), which also
performs the role of sharpening neural selectivity for the
frequency of the spectral notch.
B. The Binaural System: the Basis for Sound
Localization in the Horizontal Plane
FIG. 5. The neuronal basis for analysis of spectral cues. A: hypothetical model of circuits involved in spectral analysis at the level of the
DCN (A1) and the IC (A2). Horizontal line at the bottom indicates array
of tonotopic inputs to DCN/IC. II, type II unit; IV, type IV unit; INH,
inhibitory input with below-BF frequency tuning; O, prototypic type O
unit; WBE, wide band excitatory input; WBI, wide band inhibitory input.
[A1 modified from Nelken and Young (164); A2 modified from Davis et
al. (49).] B: response maps of a DCN type IV unit (left column) and an IC
type O unit (right column) to pure tones (top panels) and notched noise
(bottom panels). Gray regions depict excitatory discharge rates, and
black regions indicate inhibitory discharge rates (relative to spontaneous rates, indicated by horizontal lines). [From Davis et al. (49).]
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The two binaural cues employed in sound localization tasks in the horizontal plane, ILDs and ITDs, are
usually considered to be processed separately by neurons
in the two principal nuclei of the SOC, the lateral and
medial superior olives (LSO and MSO, respectively). Under the relatively simple assumptions of the duplex theory
(192), and the long-standing, yet erroneous, assumption
that mammals inherited tympanic ears from reptiles with
hearing limited to the low-frequency range, Masterton
and Diamond (1967), in a seminal paper (141), set the
theoretical frame for many years of research in binaural
processing. These authors suggested that the MSO was
initially well developed in all mammals but was gradually lost in those mammals that subsequently evoked
high-frequency hearing only, for example, in echo-locating bats. In contrast, the LSO, concerned only with
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the processing of ILDs at high frequencies, was underdeveloped in mammals with largely low-frequency hearing, and in humans may even be absent altogether (for
details, see sect. IIIB1). Despite this attractively simple
perspective, however, evidence from the fossil record
does not support the assumption of an originally reptilian-like ear in early mammals (4, 36, 37), (see Fig. 3
and sect. I). Furthermore, despite general acceptance,
the dichotomy suggested by the duplex theory is not
strict. First, significant ILDs can occur for low-frequency sounds located in the near field (21, 217). Second, extensive psychophysical evidence indicates that
sensitivity to ITDs is conveyed by the envelopes of
high-frequency complex sounds (11, 47, 94, 119, 148,
273). In this regard, recent studies have shown that
when provision is made for temporal information in the
envelopes of high-frequency modulated tones to match
as closely as possible temporal information normally
present in the output of low-frequency channels, ITD
discrimination thresholds can be as good as, and in
some cases surpass, those for low-frequency tones (12).
Taken together, these findings support the notion
that the duplex theory describes more the frequency dependence of the two binaural cues rather than an absolute
segregation into two distinct, nonoverlapping channels. In
fact, brain mechanisms processing the binaural cues appear to be present across the entire frequency range of
human hearing. To this end, the need for a refined theory
of binaural processing, one that also encompasses its
evolutionary development, appears timely. Such a theory
must also account for emerging data sets describing the
physiological nature of binaural processing, as well as the
means by which spatial cues are represented in the human brain (compare Refs. 73 and 76).
1. Neuronal mechanisms of ILD processing
From several lines of evidence, it is reasonable to
assume that ILDs were the only binaural cue used by early
mammals. 1) It appears that the mammalian tympanic ear,
when it first appeared some 200 million years ago, was
mechanically tuned to frequencies between 4 and 18 kHz
(152, 204) and subsequently evolved rapidly to incorporate higher frequencies during the early evolution of mammals (70, 203). Hence, it is likely that these animals experienced prominent ILDs suited to sound localization
across their entire hearing range. 2) All terrestrial mammals investigated thus far, including echo-locating bats,
possess well-developed LSOs that seem to correlate in
size with the range of frequencies an animal can hear
(156). 3) All mammals appear to share one common neural mechanism for processing ILDs (267),4 4) requiring
4
At least concerning the initial stage of ILD processing (see below).
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considerably less temporally precise cellular and circuit
properties than does the processing of ITDs (see below).
5) The earliest mammals were very small and experienced
ITDs produced by sound arriving directly from a source of
up to ⬃50 ␮s only (73).5 As such, the ability to process
ITDs evolved either by means of a sudden improvement in
temporal resolution of the auditory brain stem (by two
orders of magnitude) or, more likely, gradually, and consequently much later, during evolutionary development
(73, 76). 6) ITD processing, with few exceptions (64),
appears to be realized only in low-frequency hearing
mammals and, hence, in a minority of mammalian species: those that employ low-frequency communication
calls (all larger terrestrial mammals) and/or those that
reside in open environments and benefit from hearing
over larger distances, for example, to detect predators
[e.g., some desert rodents (132, 133, 258 –260)]. These
groups must localize sounds for which no appreciable ILD
is generated.
The initial site of ILD processing is generally considered to be the LSO, with LSO principal neurons innervated
by direct excitatory inputs from spherical bushy cells (SBC)
of the ipsilateral cochlear nucleus (CN) (Fig. 6, A and B;
Refs. 29, 209, 257). Bushy cells combine inputs across
several auditory nerve fibers, relaying their pattern of
nerve action potentials to neurons in the LSO. At higher
sound frequencies, these spike patterns resemble the “primary-like” patterns of primary auditory nerve fibers, characterized by a large, rapid response at stimulus onset and
a subsequent decline in response (“spike-frequency adaptation”) to a steady state over the remainder of the stimulus duration (197a). If the stimulus is modulated over
time (for instance, in amplitude), the spiking activity of
SBCs is locked to the stimulus envelope up to modulation
frequencies of at least 1,000 Hz (106). For low-frequency
sounds (up to a few kHz), SBC spiking is locked to the
fine structure of the stimulus (65, 106, 113). LSO neurons
also receive inhibitory inputs indirectly originating from
the globular bushy cells (GBCs) of the contralateral CN.
Globular bushy cells are very similar to SBCs, but with the
significant difference that they are innervated by a larger
number of ANF inputs and show, if anything, superior
temporal precision to SBCs (106, 108). They also possess
the thickest diameter axons of any nerve fiber in the
auditory system (160). GBCs project to the medial nucleus of the trapezoid body (MNTB) on the contralateral
side (89), forming synaptic contact via calyciform synapses (calyx of Held; Refs. 93, 161) onto glycinergic (262)
MNTB neurons, which in turn project to the LSO at the
same side (62, 142, 207, 226) (Fig. 6, A and B). The calyx
5
It can, however, not be excluded that, in early mammals, inter-ear
connections comparable to that in frogs and sauropsids slightly increased the range of physiological ITDs (126).
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FIG. 6. The neuronal basis underlying ILD processing. A: schematic of the mammalian ILD circuit. ILD sensitivity is first created in the LSO by
convergence of excitatory inputs from SBCs located in the ipsilateral AVCN and inhibitory inputs from ipsilateral MNTB, which is itself innervated
by GBCs of the contralateral AVCN. Projections of the LSO to the contralateral DNLL and IC are excitatory and inhibitory to the ipsilateral DNLL
and IC. In the IC, ILD sensitivity is created de novo by the convergence of monaural contralateral excitatory input from the AVCN and binaural
inhibitory input from the DNLL. B: schematic of the distribution of excitatory (red) and inhibitory (blue) input onto a LSO neuron (orange). Depicted
are somatic and dendritic areas of a LSO principal cell. C: schematic of the typical sigmoid ILD function of a LSO neuron is shown.
of Held, in combination with a battery of potassium conductances that prevent temporal summation of inputs in
MNTB cells (reviewed in Ref. 255), renders the MNTB a
high-fidelity station in the ascending auditory pathway
(95, 125, 149, 224), converting well-timed excitatory inputs into well-timed inhibitory outputs. MNTB cells also
project to a range of target nuclei other than the LSO,
including the ipsilateral MSO (see below).
The convergence of excitatory inputs from the ipsilateral CN and inhibitory inputs from the opposite CN via
the MNTB resembles a relatively simple subtraction process (159) (Fig. 6B), creating the well-described ILD sensitivity of LSO neurons (16, 26, 83, 176). These functions
are usually sigmoid in form, with neurons completely
inhibited when the sound at the contralateral, inhibitory, ear is more intense (“negative ILDs”) and maximally responsive when the sound at the ipsilateral,
excitatory, ear is more intense (“positive ILDs”) (review in Ref. 267; Fig. 6C).
Although temporally precise inputs have been demonstrated not to be required for ILD sensitivity of the
sustained response of neurons in the LSO, timing does in
fact appear to be important for generating ILD sensitivity
at stimulus onset and, generally, to LSO neurons tuned to
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low-frequency sounds (77, 101, 176). In particular, increasing evidence exists to suggest that, based on their
known excitatory-inhibitory (EI) interaction, low-frequency LSO neurons are sensitive to ITDs, with a resolution almost comparable to that of neurons in the MSO
(247). In contrast to MSO neurons, however, coincidence
of ipsilateral excitatory input with the contralateral, inhibitory input generates response minima (“troughs” in
the rate versus ITD functions); peak activity occurs when
inputs are noncoincident (or maximally out of phase in
response functions) (159, 247, 272). This issue is discussed in more detail in section III, B and C3.
As suggested above, the two major inputs to the
LSO are specialized for high-fidelity temporal transmission. Nevertheless, exquisite timing of inhibitory influences appears not to be a prerequisite for the subtraction mechanism underpinning ILD sensitivity, at least
for high frequencies where phase-locking is not an
issue. Interestingly, the contralateral input to LSO neurons must traverse a greater axonal distance to reach
the LSO including, in the process, an additional synaptic stage via the MNTB. One might therefore expect that
contralaterally derived inhibition should arrive later in
the LSO (a similar argument has traditionally been used
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GROTHE, PECKA, AND McALPINE
to explain why MSO neurons prefer contralaterally
leading sounds, potentially compensating for a longer
axonal delay). Nevertheless, Tsuchitani (1988, Ref. 249)
described the inhibitory effect in cat LSO neurons to be
strongest at onset, and to adapt during ongoing stimulation. Hence, by some means, the GBC-MNTB pathway
compensates for the longer distance contralateral axons must span before innervating their target neurons
in the LSO. Possible explanations could be the shorter
latency and larger axon diameter of GBCs compared
with SBCs (review in Ref. 209), and a minimized synaptic delay to the MNTB due to the giant calyx of Held
(review in Ref. 255). Delaying the contralateral stimulus in the range of a few hundreds of microseconds
results in the ipsilaterally generated excitation preceding the contralaterally generated synaptic inhibition
sufficiently to evoke at least a single action potential
(101, 174, 176, 178). This may be related to the wellknown phenomenon of “time-intensity trading,”
whereby ITDs leading at one ear can be used to compensate for ILDs favoring the other, and vice versa (50,
264, 274). Time-intensity trading can also be observed
neuronally (20, 77, 187, 271) and, in a significant proportion of LSO neurons, can produce different latency shifts
for the two binaural inputs, depending on the overall
intensity (101, 176; see also Ref. 271 for similar responses
in the IC). In this context, it is important to note that this
effect most likely depends on the stimulus envelope, i.e.,
largely on the overall energy accumulated, corresponding
to the integral of the envelope of the waveform rather
than the absolute sound level (92).
The LSO, which has no homolog in other vertebrates including birds, is the primary site for processing
ILDs in the mammalian auditory system. Nevertheless,
there is no reason a priori why neurons in any brain
center in which inputs from the two ears could conceivably converge onto individual neurons, should not
also constitute sites at which neural sensitivity to ILDs
is generated (Fig. 6A). Consistent with this notion, ILD
sensitivity generated de novo has been demonstrated in
experiments in which the ILD sensitivity of IC neurons
was abolished by blocking the action of GABAergic
inhibition locally (179). A likely source of GABAergic
inhibition to the IC is the cross projection from the
dorsal nucleus of the lateral lemniscus (DNLL), and
removing this connection by sectioning its projecting
axons or by pharmacological inactivation of the DNLL
itself, leads to a release from binaural inhibition in IC
neurons (24, 102, 134). Furthermore, a greater proportion of IC than LSO neurons shows ILD sensitivity that
is stable with average sound intensity (177). Whereas
ILD sensitivity in LSO neurons is characterized by sigmoidal ILD functions that shift in a systematic manner
with increasing intensity to the excitatory ear, those in
IC are less affected. This is consistent with at least
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some of the inhibitory effect in IC being derived from a
source other than the inhibitory input to the LSO (177).
Nevertheless, given the sufficiency of the LSO in producing neural sensitivity to ILDs, it seems likely that
ILD sensitivity in the majority of IC neurons reflects
LSO input, with modifications to this input provided by
mechanisms local to the IC.
Current evidence, anatomical and physiological
data from experiments conducted in a wide variety of
mammals and psychophysics of ILD processing in
mammals including humans, is consistent with the view
that brain mechanisms for processing ILDs are highly
conserved, possibly for almost 200 million years. Nevertheless, an ongoing controversy concerning underlying brain mechanisms in humans must be addressed if
this consistency is to be accepted. This controversy
relates to a number of anatomical studies seemingly
demonstrating the lack of a MNTB in the human brain
(see Appendix A). If this were true, and we argue below
that it is unlikely, humans would had to have developed
fundamentally different brain mechanisms, compared
with all other mammals, by which ILDs are processed
particularly as this important source of inhibitory input
to the LSO would be absent. That the LSO itself represents a prominent structure even in the human brain
has been confirmed by a number of anatomical studies
(9, 128, 236) and, since chimpanzees are reported to
possess an MNTB (237), the presumed loss of the
MNTB in the human lineage would have had to occur
within the last six million years. Given that every single
mammalian species examined to date possesses a
prominent MNTB, as well as an LSO, this appears unlikely indeed. Neurons in the human LSO would either
have a completely different function, or a different
source of inhibitory input compared with other mammals, a difficult proposition to sustain given that the
MNTB is the major source of contralaterally evoked
inhibition in the entire auditory brain stem. This issue
becomes even more problematic if one considers that
the MNTB is also the major source of well-timed inhibition not only for binaural circuits (including also
those involved in ITD processing, see below) but also
for monaural processing. MNTB projections to monaural neurons in the SOC, for example, are responsible for
creating transient “on” and “off” responses (72, 129).
Axons from the MNTB branch multiple times, targeting
multiple sources within the SOC and beyond (e.g., the
dorsal and ventral nuclei of the lateral lemniscus; Refs.
82, 219, 224, 225). Hence, without the MNTB, the human
auditory system would have to have evolved completely
different strategies not only for processing binaural,
but also monaural acoustic cues. In the light of the
current direct (see Appendix A) and indirect (above)
evidence, there is no reason to assume that brain mech-
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anisms underlying sound localization in humans deviate from the general pattern observed in mammals.
2. Neuronal mechanisms of ITD processing
Neural coding of ITDs demands the highest precision of any temporal process known to exist within the
mammalian, reptilian, or avian brain. In essence, neurons must resolve differences in the time of arrival of
the sound at each ear that are almost two orders of
magnitude shorter than the duration of action potentials bearing that information. Nevertheless, despite the
apparently insurmountable challenges posed by this
task, different groups of animals have, independently,
evolved the ability to use ITDs in sound localization
tasks (see sect. I). Sauropsids (“reptiles” and birds), for
example, have evolved a mechanical coupling of the
two ears that increases the magnitude of ITDs prior to
the sensory transduction process in the inner ear (97,
205). Nonetheless, these modifications aside, which appear fitted to enhance the magnitude of ITDs generated
by the size of the head, it is the exquisite temporal
precision of coincidence detection by the mammalian
MSO, and its analogous structure in birds, the nucleus
laminaris (NL) (Fig. 7A) that makes possible sensitivity
to ITDs in the submillisecond range. For important
definitions concerning ITD processing, see Appendix B.
A) THE BIRD NL. The NL receives bilateral excitation via
a systematic arrangement of axonal inputs, the so-called
delay lines (171, 180, 275), generating a map of azimuthal
space at this primary site of binaural integration (in vitro:
Refs. 111, 195; in vivo: Refs. 32, 33) (Fig. 7C). This ar-
993
rangement of coincidence detectors and delay lines accords with that envisaged by Jeffress in his seminal paper
(103) (Fig. 7C). A major addition to this basic arrangement in birds is the apparently tonic (i.e., not phaselocked) GABAergic inhibition (155, 266) that targets NL
neurons (131, 244) (Fig. 7, A and B), maintaining binaural
coincidence detection at high stimulus amplitude levels
(46, 63, 184) and/or compensating for ILDs (23). This is
achieved through the depolarizing effect of a Cl⫺ outward
current that results in low-threshold K⫹ channels opening
and shunting the membrane current (63, 98, 154, 155). By
such means, monaural inputs are kept from generating
spike activity in NL at high sound levels that could, theoretically, lead to maximal spike rates even for binaural
inputs that are entirely out of coincidence (194). Moreover, a recent study in the chick indicates that axon
length, axon diameter, and intermodal distance all contribute to tuning individual delay lines to adjust ITD sensitivity of single NL neurons within the physiological
range (213).
B) THE MAMMALIAN MSO. In mammals, it appears that
neurons in both of the major nuclei of the lower auditory brain stem, the MSO and the LSO, are capable of
extracting ITD information from their binaural inputs,
although the MSO has traditionally been considered the
major site of ITD processing. Here, we first describe the
MSO, and the ITD sensitivity observed in its bilaterally
excited (“EE”) neurons. We then turn our attention to
the LSO, where ITD sensitivity is reported for neurons
excited by one ear and inhibited by the other (“IE”
neurons).
FIG. 7. The neuronal basis underlying ITD processing in birds. A: schematic of the avian ITD circuit [for the chick, modified from Burger et al.
(23)]. Coincidence-detector neurons in the NL are aligned in a thin horizontal lamina, innervated bilaterally by excitatory inputs from the NM. The
axons of NM neurons are bifurcated, one branch projecting to the contralateral NL and the other to the ipsilateral. Only the contralateral projection
is arranged in the form of an array of delay lines. GABAergic input to the NL is provided by the ipsilateral SON. B: schematic of the distribution of
binaural excitatory (red) and monaural inhibitory (blue) input to a NL neuron (green). Depicted are somatic and dendritic areas of a NL principal
cell. C: delay-line arrangement of binaural inputs (vertical lines in left panel) to NL neurons (closed circles in left panel). Note that contralateral
inputs systematically increase in axon length along the horizontal axis, giving rise to a gradient in preferred ITD (see right panel; ITD functions are
color coded according to their position along the delay axis in the left panel).
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Despite many decades of research investigating the
structure and function of the MSO [Ramon y Cajal speculated in 1907 as to the function of MSO in binaural
processing (190), and the first in vivo recordings from
MSO cells date back to Galambos et al. in 1959 (66)],
mechanisms contributing to ITD processing by MSO neurons are still not fully understood. Nevertheless, recent
studies employing a range of in vivo and in vitro techniques have extended our understanding considerably.
Here, we focus only on responses of neurons in the MSO
of low-frequency hearing mammals, although considerable evidence exists suggesting that the processing of
“envelope” ITD sensitivity in high-frequency cells follows
similar mechanisms, at least in mammals that have good
low-frequency ITD sensitivity (71). Envelope ITD sensitivity in mammals with only high-frequency hearing and its
evolution is not in the focus of this review and has been
dealt with elsewhere (78, 87; review in Ref. 73).
In most mammals with well-developed low-frequency
hearing, the MSO is a laminar structure located medially
to the more prominent LSO (190, 235) (Fig. 8A). The MSO
is organized such that neurons tuned to the highest frequency sounds lie towards the ventral pole of the nucleus,
and those tuned to the lowest towards the dorsal pole (68,
84). MSO principal cells typically show bipolar morphology and are arranged in a single para-saggital plane with
two major dendrites emerging from the soma 180° to each
other and extending orthogonally with respect to the
dorsoventral axis of the nucleus (112, 190, 191, 235) (Fig.
8, B and C). Principal cells appear to receive four major,
and highly segregated, inputs from different sites within
the ascending auditory pathway (112, 263) (Fig. 8, D and
E). SBCs from the CN on each side of the brain converge
onto single MSO neurons, with ipsilaterally derived inputs
synapsing on the lateral dendrites and contralateral inputs on the medial (117, 135, 169, 223, 235, 257). The
excitatory nature of these inputs, mediated by glutamatergic transmission, has been confirmed by means of in
vitro recordings (34, 80, 81, 136, 211, 222). In addition,
MSO neurons also receive bilateral inhibitory inputs (80,
81), largely restricted to the somata of MSO neurons (38,
112, 186, 263) (Fig. 8C). Interestingly, this restriction only
arises during a period of developmental refinement following the onset of hearing (112, 263), and species in
which low-frequency ITD processing is absent do not
show this refinement (112, 252). These inhibitory, glycinergic inputs (112, 227, 262) originate in the MNTB (28, 130,
235, 263) and the lateral nucleus of the trapezoid body
(LNTB) (30). Input from the MNTB, which is driven by
stimulation of the contralateral ear, as well as input from
the ipsilaterally driven LNTB, have been shown to evoke
inhibitory postsynaptic potentials (IPSPs) in MSO cells in
vitro (34, 80, 81, 136), and local application of glycine in
the MSO by means of iontophoresis blocks spiking activity in vivo (18, 181). Both the MNTB (as discussed in sect.
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and the LNTB show morphological specializations for
fast and high-fidelity synaptic transmission, their calyceal
structure being one such example [MNTB input (255) and
end bulbs, LNTB inputs (227)].
An absolute requirement for ITD sensitivity is the
ability to generate and retain information concerning the
fine-structure waveform of the sound arriving at each ear
independently, at least until the primary stage of binaural
integration in the brain stem. Primary auditory nerve
fibers (ANFs) synapsing at the base of the inner hair cells
(IHCs) of the cochlea respond to the cycle-by-cycle
changes in the IHC membrane potential (itself reflecting
the back-and-forth deflections of the stereocilia) with action potentials that are “phase-locked” to the stimulus
waveform (65, 113, 201). Phase-locking in ANFs degrades
with increasing frequency with a pronounced roll-off
above 2–3 kHz (106), although fibers along the full length
of the basilar membrane show phase-locking if they are
capable of responding to a low-frequency stimulus (reviewed in Ref. 267). Note that the limitation to phase
locking does not arise in the ANFs per se (90). Rather, it
reflects the reduction in capability of the receptor potential of the IHCs to follow the cycle-by-cycle deflection of
the stereocilia at increasing stimulation frequencies. This
low-pass feature of the IHCs provides an upper limit for
which temporal information is theoretically accessible in
the mammalian brain. Accordingly, the upper frequency
limit at which mammals can resolve the ITD in the signal
fine structure lies between 1 and a few kHz (119).
Since MNTB cells are also known to phase-lock their
output to low-frequency pure tones (51, 95, 125, 149, 173,
224), at least three of the four MSO inputs provide precise
temporal information. Based on the anatomical specializations of the LNTB and its input (228), we can speculate
that this input is also phase-locked (high-frequency LNTB
cells in the bat are able to follow fast fluctuations of the
envelope similar to MNTB cells, Ref. 78). However, despite decades of research, it remains unclear how the four
inputs to MSO neurons interact to produce the well-described ITD sensitivity of MSO neurons, and how ITD
sensitivity of single MSO neurons provides for a meaningful representation of auditory spatial cues. In large part,
this is due to the technically demanding nature of in vivo
recordings from low-frequency MSO cells, most likely as a
result of the high degree of myelination of input fibers
(161), the strong neurophonic potential generated by their
phase-locked synaptic input (162, 269), and the possibility
that action potentials are generated some distance from
the soma along the axon (211). Similarly, in vitro recordings from acute brain slices, the only means so far by
which the cellular properties of MSO and its inputs can be
investigated, grow rapidly more difficult with each day
following hearing onset. As a result, almost all intracellular recordings have been performed in immature brain
tissue, and while these are vastly valuable to the underIIA)
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995
FIG. 8. The neuronal basis underlying ITD processing in mammals. A: drawing by Ramon y Cajal (1907, Ref. 190) depicting input pattern to (from
left to right) LSO and MSO as well as calyces of Held terminating in the MNTB. B: drawing by Ramon y Cajal (1907, Ref. 190) depicting MSO principal
cells (dark black) extending dendrites in a bipolar fashion. C: confocal picture of a section through adult gerbil MSO. Staining for glycine receptors
(yellow) is restricted to somatic areas of MSO neurons. Dendrites (blue, MAP2 staining) are mostly devoid of glycine receptors. D: schematic of the
mammalian ITD circuit. MSO principal cells (yellow) receive binaural excitatory inputs (red) from SBCs in the ipsilateral and contralateral AVCN
as well as binaural inhibitory inputs (blue) from the LNTB and MNTB. MSO neurons send excitatory projections to the DNLL and IC. E: schematic
of binaural excitatory (red) and binaural inhibitory (blue) synaptic input distribution onto a MSO neuron (yellow). Depicted are somatic and
dendritic areas of a MSO principal cell. F: schematic of typical ITD function for a MSO neuron.
standing of the cellular basis of coincidence detection in
the microsecond range by MSO neurons, many questions
remain to be answered.
That the MSO is the main structure for ITD coding is
supported by the fact that albino cats exhibit a pronounced atrophy of MSO neurons (40, 41) and, at the
same time, show strong behavioral deficits in azimuthal
sound localization (91) as well as diminished ITD sensitivity at the level of the auditory midbrain (268). It has
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been known for many years that low-frequency MSO neurons respond to pure-tone stimulation with phase-locked
discharge patterns (7, 18, 44, 66, 68, 181, 231, 269) and are
sensitive to ITDs in the stimulus fine-structure (cat: Refs.
26, 66, 269; dog: Ref. 68; kangaroo rat: Refs. 44, 162; gerbil:
Refs. 18, 181, 231; rabbit: Ref. 7).
Based on their apparent binaural excitatory (“EE”)
characteristics, some MSO neurons are responsive to
monaural stimulation of either ear alone, but the sum of
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GROTHE, PECKA, AND McALPINE
the two monaurally evoked responses is generally far
below the response to binaural stimulation at favorable
ITDs (269). In addition, binaural stimulation at favorable
ITDs normally evokes far higher degrees of phase-locking
than stimulation at unfavorable ITDs (7, 26, 44, 68, 231,
269). Moreover, the best ITD (BITD, the ITD eliciting
maximal spike rates) can be predicted from the phase
delay of the two monaural responses (68, 78, 231, 269).
The tuning of MSO neurons for sound frequency is also
apparent: the highest spike rates (and greatest modulation in the response) are generally evoked by pure tones
presented at a neuron’s characteristic frequency (CF).
Shifting the pure-tone frequency away from the CF in
either direction results in a systematic reduction in the
maximum spike rates elicited, and a concomitant reduction in the modulation depth of the ITD functions, i.e., a
reduction in the dynamic range of the spike rate elicited
by different ITDs (18, 181, 231, 269) (Fig. 9A). Consistent
with theoretical outcomes of Jeffress’ (1948) model (103),
many MSO neurons show a characteristic delay (CD): an
ITD for which the relative discharge rate is identical for
different stimulus frequencies (202, 272). This is illustrated in Figure 9A, which shows the responses of an MSO
neuron to pure tone stimulation for five different sound
frequencies. Each pure tone frequency, when presented
with a range of static ITDs imposed on the stimulus
waveform, evokes a cyclic pattern of responses; response
maxima occur at intervals separated by the period of the
stimulus waveform, reflecting the underlying mechanism
of binaural coincidence detection. Theoretically, for neurons with a pure axonal conduction delay from one or
both ears, the CD corresponds to the ITD at which response peaks are aligned for all stimulus frequencies to
which the neuron is sensitive. This would constitute a
pure time delay for the coincidence detector as suggested
by the Jeffress model (7, 231, 269) (Fig. 9B1). ITD-sensitive neurons of the LSO represent a variation on this
theme, showing a frequency-independent trough in their
response (when ipsilateral excitation and contralateral
inhibition coincides), consistent with their “EI” inputs
(Fig. 9B3, see also sect. IIIB2C). However, CDs are often
not found at response peaks (or troughs), but rather tend
to align along the slopes of the ITD functions (Fig. 9, A
and B2) (68, 202, 234). This suggests that ITD sensitivity
in these neurons is not generated by a pure time delay
mechanism but that additionally a form of phase delay is
present, which is not explained with simple, equally tuned
“EE” and “EI” inputs as suggested by the Jeffress model.
Given the anatomical evidence for both excitatory and
inhibitory inputs onto MSO neurons, it may not be surprising that many cells with such “intermediate” characteristics have been observed (7, 8, 181). Thus it may be
more accurate to describe ITD sensitivity as comprising a
continuum between the extreme pure peak type, or “EE,”
and pure trough type “EI” characteristics (61). Nevertheless, the relative stability of the BITD as a function of
frequency underlying the notion of a characteristic delay
is predicated on the concept of purely excitatory coincidence detection and, combined with its predictability
based on the monaural responses, has been taken as
evidence for, if not definitive proof of, an underlying
mechanism similar to that proposed by Jeffress’ 1948
model (103).
Despite its general acceptance, an increasing number
of studies report findings that are inconsistent with the
standard Jeffress model. These findings relate to a range
of different anatomical and physiological aspects of ITD
processing, as well as the nature of any neuronal representation of ITDs. The latter is discussed in detail in
section IIIC2, but at this juncture, one important consideration is the apparent departure of the distribution of
BITDs from model predictions. The Jeffress model proposes an azimuthal space map based on the BITDs of an
array of coincidence detector neurons. Hence, BITDs
should lie largely within the physiological range of ITDs
FIG. 9. Characteristic delay (CD) and characteristic phase (CP). A: example recording of ITD functions from a neuron in the gerbil MSO for
five different sound frequencies. When presented with frequencies below or above the BF of the cell (250 Hz), the maximal response rate and
dynamic range decreased. The CD of the neuron (238 ␮s) is denoted by the arrow. [Modified from Pecka et al. (181).] B1–B3: schematic
representation of ITD functions with identical CDs (marked by arrows) but at different relative response rates. ITD functions at BF are depicted
in gray, while light gray and black represent stimulation frequencies above and below BF, respectively. For details see text.
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
(humans: ⫾690 ␮s, Ref. 157; gerbils: ⫾135 ␮s, Ref. 138),6
and potentially with greatest density in the region of
highest psychophysical resolution (and ethological relevance) around 0 ITD. Such a pattern conforms to descriptions of ITD coding in the avian brain (see sect. IIIC1) but
has not been confirmed for mammals. Indeed, BITDs
appear not to be restricted to the physiological range (or
at least predominantly within it, again as found in birds),
but often lie beyond it, at ITDs greater than would be
created by the interaural distance. This is based on solid
population statistics at different levels of the ITD coding
pathway such as the IC of the guinea pig (146), cat (86),
and chinchilla (246); the MSO of the kangaroo rat (44)
(although not discussed there) and gerbil (18, 181; see Fig.
9A1); as well as the dorsal nucleus of the lateral lemniscus in the latter (219). Furthermore, there appears to be
little difference in the distribution of BITDs between species with different interaural distances (cf. cat and guinea
pig, Refs. 172, 246). Moreover, neurons in the MSO of the
dog, described in some detail by Goldberg and Brown
(68), show BITDs far beyond the range of ITDs predicted
by the animal’s head width, and Kuwada and colleagues
(60, 61) reported many, if not the large majority (judging
from their Fig. 8 in Ref. 61, for example), of ITD-sensitive
“peak-type” cells in the lateral lemniscus having BITDs
outside the rabbit’s physiological range. In relation to the
Jeffress model, this creates two conceptual problems.
First, the large number of cells with BITDs beyond that
predicted by the size of the head requires explanation.
Second, in the absence of any other delay mechanism, the
coding of these exceptionally long BITDs would require
substantial differences in axonal path-lengths from each
ear to individual MSO neurons.
Related to the first conceptual problem, the existence
of BITDs outside the range predicted by the head size
could be explained by the need to process reverberations
that result in reduced correlations of the phase-locked
inputs between the two ears (59). In fact, the mixing of
multiple direct and indirect sound sources that results in
reduced interaural coherence (15) produces rapidly fluctuating ITDs and ILDs that can greatly exceed the “physiological range” (150). In such cases, neural mechanisms
for detecting reduced interaural coherence could exist in
the form of coincidence detectors wired for longer delays.
Nevertheless, such long ITDs are relatively rare in most
natural environments and their importance lessened by
relatively long integration times at higher auditory stations. There appears no particular reason why the mammalian auditory system might devote the majority of its
ITD-sensitive neurons to the processing of interaurally
decorrelated sounds or fluctuating ITDs that do not
6
Note that the actually occurring ITD at a given head to some extent
depends on sound frequency (246).
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997
indicate a specific source location, as well as the questions as to why this does not appear to be the case in
birds. Interestingly, and as mentioned above, there is
no obvious difference in the distribution of BITDs in
small mammals like gerbils or guinea pigs and the much
larger cat (172, 246). Rather, BITDs depend on the frequency tuning of the ITD-sensitive cells, i.e., the CF (the
frequency with the lowest tone-evoked threshold). Based
on a large population of guinea pig IC neurons, McAlpine
et al. (146) first pointed out that the average BITD increases with decreasing CF and, in fact, shows an almost
constant best IPD. Such a constant BIPD has also been
shown for the gerbil MSO (18, 181) and dorsal nucleus of
the lateral lemniscus (219), although only with tonal stimulation, and for the cat IC (86). The conceptual implications on coding strategies of ITD in mammals are discussed in section IV. But it should be noted here that the
observed dependency of BITD on CF is hardly compatible
with the idea of a labeled line coding of auditory space
assumed in Jeffress’ model.
The second conceptual problem in the context of the
Jeffress model that arises from the existence of long
BITDs concerns the existence of delay lines per se and the
requirement for exceptionally long delay lines originating
from the contralateral ear (60). What mechanism could
account for the actual delays observed for contralateral
inputs responsible for generating neural BITDs, almost all
of which correspond to stimulus locations in the contralateral hemisphere (sound leading at the contralateral
ear)? The traditional textbook notion is that the internal
delay mechanism is realized by means of specific combinations of the axonal length of the binaural excitatory
inputs. As obvious as it is in the bird NL, the anatomical
arrangement of MSO inputs on the contrary is difficult to
interpret. Some inputs may resemble delay-line arrangements as proposed by Jeffress (223), but the interpretation of these single projections is problematic (compare
Ref. 74). A detailed anatomical analysis comes from Oliver and colleagues (10) who performed a complex reconstruction of small tracer injections into the CN. Their
results include an analysis of the axonal diameter of
individual fibers and suggest some form of graded input
from the contralateral side where, in some reconstructions, shorter collaterals tended to innervate more rostral
parts of MSO and longer collaterals more caudal. However, other injections revealed very restricted terminal
fields or even gradients running in the “wrong” directions.
Accordingly, the authors were very careful in their conclusions and suggested that “other factors may be involved in the computation of ITDs.” Most exactly, as
stated above, the calculated delays would, in some cases,
fit the Jeffress model with ITDs only within the physiological range, but definitely would not account for the
observed long delays. Hence, axonal length, although
likely an important factor in generating delays, appears
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not to be systematically arranged and cannot account for
the long delays observed physiologically. In this sense, the
situation is fundamentally different from that in birds.
Interestingly, a factor that has received little attention
until lately is the distance of nodes of Ranvier and the
influence of axon diameter, which could, if varied from
axon to axon or at different axonal branches, easily contribute to a substantial delay (42); accordingly, data from
the chick brain stem indicate a significant contribution of
internode distance (213).
Another form of physical delay that has been proposed to contribute to ITD processing is the cochlear
delay (208). Due to the limited propagation speed of the
traveling wave within the cochlea, moving from basal
(high frequencies) to apical (low frequencies), the response latency to an acoustic event, for instance, a very
brief click that activates inner hair cell transmitter release, occurs at increasingly longer delays relative to the
stimulus onset for progressively lower frequency regions
along the basilar membrane. Schroeder’s notion that an
interaural mismatch in the frequency tuning of the inputs
to MSO neurons could be responsible for generating ITD
delay tuning (Schroeder 1977, Ref. 208) was popularized
by Shamma (216) and has been revisited by Joris and
colleagues in recent years (104, 109). However, it must be
stated that no convincing evidence for the employment of
such cochlear delays in the tuning of neurons to a preferred ITD has been provided.
Yet another means by which internal delays could be
generated, and by which the experimentally observed
phase delays could be explained, is synaptic inhibition. As
discussed above, the MSO receives bilateral inhibitory
inputs that employ glycine as their neurotransmitter.
These inputs are highly specialized for high-fidelity and
high-precision (i.e., phase-locked) temporal transmission.
In vivo experiments combined with pharmacology demonstrate that blocking glycinergic inhibition with strychnine results in a broadening of the ITD tuning function
towards ipsilaterally leading ITDs resulting in a shift of
the best ITD towards 0 (to the “left”; for details, see
Appendix C) (18, 181). This suggests that inhibition plays
a crucial role in the ITD tuning of MSO neurons. Moreover, a “leftward” shift of the best ITD is also observed
when endogenous inhibition, rather than being blocked, is
supplemented through iontophoretic application of glycine onto MSO neurons. However, this shift, most likely,
arose due to disruption of the normal timing of the glycinergic inputs (for details, see Appendix C). Together,
these results suggest that it is not only the inhibition as
such that tunes the ITD function, but its timing relative to
the timing of the excitatory inputs (181). A detailed explanation of the findings and the suggested underlying
mechanism is given in Appendix C.
An important consideration for the role inhibitory
inputs in tuning neurons for their preferred ITD is the
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possibility of adjusting or refining the contralateral delay
during ontogeny. Anatomical refinement of the glycinergic inhibition has been shown to be dependent, at least
partially, on auditory experience during early development. Raising gerbils in omni-directional noise, which
masks most spatial cues (265), reduces the degree of
synaptic selection of glycinergic MSO inputs during what
appears to be a critical period shortly following the onset
of hearing (112, 263). In animals subject to such deprivation, the distribution of BITDs deviates significantly from
that in control animals; BITDs are, on average, much
closer to 0 ITD than in normally reared animals (212).
These findings are consistent with the interpretation that
other mechanisms (axonal length, cochlear delays, etc.)
establish an approximate BITD but, following the onset of
hearing, an experience-dependent process selectively enhances inhibitory inputs to further tune BITDs to the
desired population mean. Moreover, by changing the balance of excitatory and inhibitory inputs (compare Ref.
137), it is possible that BITDs might also be adjusted
under dynamic control as needed (e.g., in noisy environments with many concurrent sounds).
C) ITD SENSITIVITY IN LOW-FREQUENCY LSO NEURONS. Interestingly, although controversial with respect to MSO input
(see Appendix C), there is no debate over the significance
of phase-locked inhibition from the MNTB contributing to
the ITD sensitivity of low-frequency LSO neurons. As
described in section IIIB1, the “EI” connectivity of LSO
neurons is primarily thought to subserve the processing of
ILDs in high-frequency sounds by a process of simple
subtraction. Nevertheless, even though ILDs are of marginal importance for low-frequency sound localization
(save for situations of near-field stimulation), an entire
limb of the LSO appears dedicated to the processing of
low-frequency sounds in many species. Previously it was
considered that low-frequency LSO neurons were only
weakly sensitive to ILD, or even monaural in their responsiveness, because they lacked contralateral inhibitory input (16, 26, 83, 231, 248). However, Finlayson and Caspary
(58), in a comprehensive study in the chinchilla, found
that low-frequency LSO neurons (CFs ⬍1,200 Hz) were
not only sensitive to ILDs, but also to phase-inversions of
an acoustic stimulus, suggesting that they might additionally be sensitive to ITDs/IPDs in the fine-structure of
low-frequency sounds (Fig. 10A). This notion was subsequently verified by Tollin and Yin (247) (Fig. 10B) in the
first study to record systematically the responses of lowfrequency LSO neurons of the cat to ITDs in the stimulus
fine-structure. This study also provided direct evidence to
corroborate the notion that LSO neurons generate the
trough-type ITD sensitivity expected from phase-locked
EI interactions.
It is worth noting at this point that these findings
strongly suggest that the inhibitory inputs from the contralateral ear (via GBCs and the MNTB) arrive simulta-
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FIG. 10. ITD sensitivity in the LSO. A: the response rate of rat LSO neurons depends on the phase of the binaural stimulus. Dependence of
binaural inhibition of a rat LSO neuron on interaural phase difference of a low-frequency tone (719 Hz). Binaural inhibition was maximal at ⬃230°
and minimal at 100°. [From Finlayson and Caspary (58).] B: sensitivity of a low-frequency cat LSO neuron on interaural level difference (ILD) and
interaural phase difference (IPD). The neuron was stimulated with binaural beat stimuli at its characteristic frequency, 566 Hz. 1: The IPD sensitivity
of the neuron is visible in the binaural-beat histograms (left) and in the period histograms (right) derived from it. The IPD sensitivity of the neuron
can be converted to an equivalent ITD sensitivity by dividing the IPD by the stimulus frequency. 2: Noise delay function created by plotting the mean
discharge rate as a function of the ITD of a broad-band noise presented to the two ears with equal amplitude. Negative delays indicate that the
contralateral stimulus lags the ipsilateral stimulus. [From Tollin and Yin (247).]
neously with the ipsilateral excitatory inputs (via SBCs) at
the LSO to suppress any responses, although the inhibitory inputs feature a longer pathway and an additional
synapse. Possible explanations for this faster contralateral conduction are discussed in section IIIB1.
D) ITD PROCESSING OF BROADBAND SIGNALS. ITD sensitivity,
whether the result of EE or EI mechanisms, is observed
not only for the fine-structure, or carrier, of low-frequency
sounds, but also for the envelope of high-frequency or
broadband sounds, and significant insight into the relative
contribution of carrier and envelope ITD sensitivity has
been obtained using signals such as interaurally delayed
broadband noise. Response functions generated to interaurally delayed noise (noise delay functions, or NDFs) are
of a damped, oscillatory shape (Fig. 11), and the central
peak of the response, in terms of its shape and preferred
ITD, is approximated reasonably well by the linear summation of delay functions obtained to pure-tone stimulation (269, 270). In a combined study of auditory-nerve
responses and ITD-sensitive neurons in the IC of the cat,
Joris (105) demonstrated that the shape of NDFs is determined both by the neural sensitivity to the fine-structure
of the low-frequency components of broadband stimuli,
and by the sensitivity to envelope features generated by
the bandpass filtering of the cochlea. Intriguingly, envelope sensitivity was not restricted to neurons with relatively high CFs, but was also present in neurons with CFs
in the low-frequency, phase-locking range, extending even
below 1 kHz [a finding recently supported by Agapiou and
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McAlpine (2)]. Joris and colleagues (107, 110) subsequently investigated the extent to which damping of the
NDFs reflects the spectral bandwidth over which binaural
coincidence detection occurs. Whilst finding strong correlations between the two measures, the data also indicate that the peripherally generated envelope sensitivity
cannot completely explain the extent to which such
damping is observed, as transitions from fine-structure to
envelope sensitivity occurred for IC neurons with CFs ⬃1
kHz lower than is observed in ANFs (105, 107). Hence,
higher level transformations such as convergence are expected to enhance envelope sensitivity in the IC, influencing the precise form of the NDFs (2).
C. Neuronal Representation of Auditory Space
1. The auditory space map in birds
A systematic map of auditory space is known to exist
in the optic tectum of the barn owl (OT, corresponding to
the mammalian SC). This “space map” is actually conveyed to the OT from the external nucleus of the IC (ICX);
as Knudsen and Konishi first reported in their seminal
paper in 1978, the receptive fields of ICX neurons shift
systematically both in azimuth and elevation along the
posterior-anterior and dorso-ventral axis of the nucleus,
respectively (122). It was later shown that the auditory
space map is formed in the ICX by convergence of ILDand ITD-sensitive inputs from the lateral shell of the
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FIG. 11. Noise delay functions to correlated and anticorrelated
stimuli. Example recordings of delay functions in response to correlated
(solid line) and anticorrelated noise (dotted line) for two DNLL neurons.
Gray shaded area depicts physiological range. Characteristic frequencies (CFs) of the neurons are shown at the top left of each panel. Note
the differences in damping of the side peaks.
central nucleus of the IC coding for the same region of
auditory space. Moreover, these converging projections
combine their input across a wide range of CFs (39, 240),
pooling that is crucial in overcoming phase ambiguities
that arise for narrow-band signals in the relatively highfrequency range employed (uniquely) by the owl in soundlocalization tasks using ITDs (122, 143, 240). The headcentered auditory space map in the OT is then merged
with that of the visual space map7 (120), ultimately providing the anatomical substrate for the pronounced audiovisually driven head-saccade reflex of the barn owl. Knudsen and colleagues went on to show that the visual input
provides instructive signals for the calibration of the auditory map during maturation (for review, see Ref. 121).
Hence, the formation of the auditory space map is
strongly related to that of the visual system, and it may
not be surprising, therefore, that the neural representation of the auditory world resembles that of the visual
world. It is well established that in owls the topographically ordered arrangement of auditory space is present at
the level of the NL, the initial site of ITD processing (33,
7
Note that the barn owl is not capable of moving its eyes, hence does
not perform eye saccades.
Physiol Rev • VOL
185, 239)), and recent data (127) suggest a similar arrangement in the chicken (Fig. 12, A–C).8
As in other birds, ILD sensitivity in barn owls is
initially encoded in the lateral lemniscus via a reciprocal
inhibition between the lemniscal nuclei on opposite sides
of the brain. Already at this level of processing there
exists a systematic gradient of ILD sensitivity and, hence,
a rough topographic map of ILDs (31, 139, 242, 243).
However, barn owls are clearly an exception in that they
belong to the group of so-called “asymmetrical owls,”
having the two outer ears and ear canals located at
slightly different positions and pointing into different vertical directions (153, 165, 253). This asymmetry results in
iso-ILD contours in the frontal field being tilted by almost
45 degrees compared with the vertical alignment found in
animals with symmetrical ears. Thus, in barn owls, ILDs
serve to encode the elevation, rather than the azimuth, of
a source location. To this end, the representation of ILDs
in these birds is almost orthogonal to the representation
of ITDs, which are unaffected by the asymmetry. By
means of a multiplicative interaction of ITD and ILD
sensitivity at the level of the auditory midbrain (182),
“classical” two-dimensional auditory-spatial receptive
fields are created (183). These are then projected, and
systematically arranged, in a two-dimensional map of auditory space in the barn owl tectum (17, 67, 122).
An interesting feature of the auditory space maps in
the owl OT is the fact that individual cells are relatively
coarsely tuned (⬃20° on average) compared with the
behavioral acuity of ⬃2–3° (6, 120). Takahashi and colleagues (5, 241) pointed out that this apparent discrepancy can be overcome by the analysis of spike rate
changes (scaled to their variance) in individual neurons
with changes in sound location, i.e., changes in spike rate
along the slope of the ITD functions. This idea is in line
with the theoretical framework of optimal coding posited
in recent years (25, 88). Hence, the systematic map of
ITDs in the owl brain stem and midbrain is undisputed,
although the nature of the associated neural code is still
open to debate.9
2. The representation of binaural cues in mammals
The topographic arrangement of auditory space represented in the avian OT has a counterpart in the mammalian SC, with a systematic arrangement of ILD sensitivity extending along the mediolateral extent of the nucleus, creating a space map (review in Ref. 114). However,
8
Recent evidence indicates that in the barn owl forebrain ITD-sensitive neurons are not arranged in an orderly map (39), and the distribution of BITDs is similar to that in small mammals, with the steepest
slopes clustering around the midline (256).
9
Actually, broader tuning of neurons relative to behavior is not a
special feature of the sound localization system but rather a ubiquitous
feature of sensory systems.
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1001
FIG. 12. The representation of auditory space in birds and mammals. A: in birds, the location of sound sources in the horizontal plane is encoded
by labeled lines originating in the NL. Neurons in isofrequency laminae of each NL (closed circles) vary systematically in their preferred ITD, with
different neurons encoding different locations ranging from midline to contralateral 90° (as illustrated by the color code). Locations near midline
are represented by neurons in either NL, giving rise to a higher resolution for medial locations compared with lateral locations. Schematic includes
only one isofrequency lamina. B: example of systematic shift of best ITDs along a iso-frequency axis of the chick NL. C: distribution of best ITDs
in the chick NL as a function of BF. D: in mammals, locations in the horizontal plane are encoded by two hemispheric channels with MSO neurons
responding maximally to stimuli positioned far in the contralateral hemifield. Nevertheless, spatial acuity is best near midline due to the position
of the steepest slope of the function being positioned near midline. E and F, top panels: example recordings of neurons with varying BFs from the
gerbil MSO and guinea pig IC, respectively. Shaded areas denote physiological range of ITDs. Note that best ITDs increased with decreasing neuronal
BF. Bottom panels: distribution of best ITD as a function of BF in the MSO and IC, respectively. Best ITDs of functions shown in top panels are
depicted in respective colors. Shown in black solid line is the function [best ITD ⫽ 0.125/BF]. Shaded areas denote physiological range of ITDs for
the gerbil and guinea pig, respectively. [A and C from Koppl and Carr (127); E modified from Pecka et al. (181); F from McAlpine (144).]
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several significant differences exist between the representations of acoustic-spatial features in barn owls and mammals. Most notably, the convergence of ITD and ILD cues in
the barn owl’s OT, from neurons with similar frequencytuning characteristics in the IC, is absent in mammals; by
and large, sensitivity to fine-structure ITDs is absent for
any frequency at which an appreciable ILD would be
generated (except for near-field situations). Indeed,
Campbell et al. (27), using the technique of “virtual acoustic space” (VAS), demonstrated a lack of any contribution
of ITDs in the SC’s representation of auditory space.
Notably too, animals deprived of visual input show abnormal arrangements of ILDs in the SC (115), although they
do not show deficits in sound localization and, indeed,
may actually show improved performance (116). Furthermore, the initial substrate from which a topographic mapping of auditory spatial cues might be developed, a representation of preferred ITDs and ILDs, ordered or otherwise, appears not to exist in the mammalian brain stem
(see below), although the existence of a visually guided
space map based on ILDs in the SC is not disputed.
A) THE NEURAL REPRESENTATION OF ILD. A systematic representation of ILD has often been assumed (193) to exist
in the mammalian LSO, but has never actually been demonstrated. At the level of the LSO and the IC, some studies
suggest a clustering of neurons with the same preferred
ILD sensitivity [overlying slopes of ILD functions in neurons recorded close to each other (16, 188)], and anecdotal reports exist of single electrode penetrations in
which ILD functions systematically varied along the penetration (261). Because ILD functions are sigmoid and not
Gaussian or sinusoidal, LSO neurons do not show closed
receptive fields as such. Rather, their sensitivity to ILDs
follows a sigmoid function with a slope across a range of
ILDs often corresponding to frontal, or near frontal,
space, resulting in a dynamic range of ILDs where small
changes in ILD produce relatively large changes in spike
rate. These slopes may shift significantly in individual LSO
neurons (or their target neurons in the IC) when manipulating stimulus parameters such as spectral content (3,
75, 100), duration (170), temporal pattern (75, 123, 124), or
intensity (100, 177, 188) and the recent stimulus history
(see sect. IIIC3). Hence, LSO neurons do not code for
absolute positions in space in the manner of a “labeledline” code but, rather, the overall relative activation of the
left and the right ILD pathways, which appears stable
across the population of ILD sensitive neurons (177),
likely encodes the source location.
B) THE NEURONAL REPRESENTATION OF ITD. In contrast to
birds, there is little evidence in mammals for any organization in the brain that provides for topographically ordered
maps of ITD. This may not be altogether surprising; evidence for an orthogonal arrangement of preferred ITDs with
respect to the main tonotopic (frequency) map in the MSO is
Physiol Rev • VOL
weak at best.10 Moreover, the projection pattern of the MSO
to the IC would imply that this suggested organization
in the MSO is not maintained in the IC (168). Nevertheless, the absence of a demonstrably ordered map of
acoustic space based on ITDs does not necessarily
preclude the existence of a less-ordered organization
were it not for compelling evidence suggesting that the
arrangement of preferred ITDs in the IC runs parallel
with, rather than orthogonal to, the tonotopic gradient.
As described in section IIIB2, values of BITDs are negatively correlated with neuronal CF. The consequence of
this for the neural representation of ITDs in mammals is
shown in Figure 12, E and F, bottom panels, which plots the
distribution of peak ITDs as a function of neural tuning for
sound frequency for MSO and IC. The demonstration by
McAlpine et al. (146) that ITD tuning is CF dependent
marked the beginning of a significant departure from the
notion that ITD is represented in the form of a labeled-line
code, whereby neurons are sharply tuned to an ITD by virtue of
their peak response (i.e., response maximum) and the tuning
is systematically varied to cover the entire physiological
range (Fig. 12, B and C). To date, the relationship between
CF and preferred ITD has been shown for the IC of the
guinea pig (146, 215), the cat (86), and the chinchilla (246) as
well as the DNLL of the gerbil (219); it evidently does not
represent specific processing at secondary stages as it has
been reported for the MSO itself of the gerbil (18, 181) (Fig.
12E). Based on these findings, the current authors earlier
postulated a reconsideration of the mammalian system emphasizing the encoding of spatial positions by changes in
spike rate across the span of “physiological” ITDs in the
entire population of homogeneously (in terms of BIPD) and
broadly-tuned (due to their low CFs) ITD-sensitive neurons
(145): neurons with the lowest CFs have, necessarily, the
broadest ITD functions in response to interaurally delayed
signals; even for relatively large changes in ITD, encompassing perhaps the entire range experienced by a small mammal
such as a gerbil, the response near the peak of the function
may change only very slightly. As such, positioning the peak
of the ITD function at long ITDs, beyond the ecologically
relevant range, places the sensitive slope of the function
where greatest ITD discrimination is required. By shifting
the peak ITD closer to zero for neurons as CF increases, the
position of the slope through the range of relevant ITDs is
maintained (Fig. 12, D–F). Accordingly, the steepest portions of the slopes were found to align around midline both
in MSO, DNLL, and IC (86, 146, 181, 215, 219). It has also
been shown that such alignment allows for high-resolution
ITD discrimination both on the single cell and population
level (214, 220). This coding strategy, referred to as two chan-
10
The apparent correlation of BITDs and rostrocaudal position in the
cat MSO (269) was not statistically significant and had not been corrected for CF.
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
nel model, stands in contrast to the labeled-line arrangement, in
which spatial positions are encoded in the specific activity
patterns of only a few identified neurons within an array of
heterogeneously (in terms of BIPD) and sharply-tuned (due to
their high CFs) neurons. It should be stressed that the two
paradigms do not necessarily differ in the coding strategy at the
single-neuron level, as spatial discrimination is maximal along
the slope of the neurons’ tuning curve regardless of coding
strategy (given a moderate response variability, compare Refs.
25, 69, 88, 241). Rather, the significant difference is given by the
fact that in low-frequency hearing mammals with comparatively small head-widths, the distribution of BITDs suggests an
encoding of spatial positions by the (average) response rate of
the entire population of neurons and not by the sparse activity
of few identified neurons (as, e.g., observed in the high-frequency hearing barn owl).
1003
citatory and inhibitory inputs, heavily label for GABAB
receptors. GABAB receptors are coupled to G proteins
and provide a mechanism for slow adjustment of synaptic
efficacy (reviewed in Ref. 43). In a recent study, Park et
al. (175) showed systematic stimulus-dependent adaptation in LSO neurons, confirming earlier evidence for
dynamic processing (57). Moreover, Magnusson et al.
(137) showed clear effects of the GABAB system on ILD
sensitivity by applying GABAB receptor agonists or antagonists to LSO in vivo: GABAB activation decreased, antagonizing GABAB increased the “receptive field” of LSO
neurons by shifting the synaptic gain and, thereby, systematically shifting the ILD function (Fig. 13). In a second
series of experiments in vitro, the same authors also
revealed the underlying mechanisms contributing to this:
upon activation, LSO neurons release GABA from their
dendrites, and this differentially regulates transmitter re-
3. Dynamics in neuronal representation
As in other sensory systems, the auditory system is
characterized not only by ascending projections, but also
by many descending connections. One class of efferent
connections seems to mainly originate in the auditory
cortex and targets auditory neurons at different levels of
the system: the medial geniculate body, the IC, several
rhombomeric structures (SOC, CN), and even the hair
cells in the cochlea. These projections are known to
influence tuning properties dependent on short-term experience and, hence, seem to be related to stimulus context (163, 238). Another class of efferent connections
arises in the SOC and targets directly inner and outer hair
cells (218). These provide a fast form of sensory feedback
that, for instance, adjusts the gain of the auditory system
to take account of overall sound intensity. The two systems may well function in concert. Until recently, the
efferent system was not considered with respect to binaural processing, and stimulus-dependent adaptation and
context dependency were typically not attributed to the
first stations of the binaural pathways. Only at the level of
the IC, stimulus-dependent adaptation has been observed
to influence binaural processing, resulting in apparent
motion sensitivity (147, 230). Moreover, although many
auditory brain stem neurons receive efferent (“context
dependent”) projections, the MSO, LSO, and MNTB principal cells seemed to be devoid of such inputs. This
appeared to accord with the notion that the MSO and LSO
constitute “hard-wired” binaural comparators that function almost like electrical circuits: highly exact and invariable. For a number of reasons, however, this view is
changing. First, evidence exists that the fast feedback
providing olivocochlear system can influence binaural
sensitivity via the lateral olivocochlear feedback system
(45). Second, evidence exists for dynamic adjustments
within the binaural nuclei themselves. MSO and LSO,
which both crucially depend on the right balance of exPhysiol Rev • VOL
FIG. 13. Dynamics in neuronal representation of sound source
location. A: their own spiking activity triggers LSO cells to release GABA
from their dendrites. GABA binds to presynaptic GABAB receptor-lowering
activity, acting preferentially on excitatory LSO inputs. B: hypothetical ILD
function showing how activity-dependent release of GABA can change the
gain and, thereby, shifts the dynamic range along the ILD axis. [From
Magnusson et al. (137).]
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GROTHE, PECKA, AND McALPINE
lease from the excitatory and inhibitory input terminals
via presynaptic GABAB receptors. Hence, at the very
least, LSO neurons are able to adjust rapidly the efficacy
of their excitatory and inhibitory inputs, altering their
binaural sensitivity in the process. The function and exact
location of GABAB receptors in the MSO are not known
yet; however, it seems likely here also that stimulusdependent dynamics might act on binaural properties
even at the first level of binaural interaction.
IV. CONCLUSIONS AND OPEN QUESTIONS
When Lloyd Jeffress published his concept on binaural
sound localization in 1948, his elegant model fundamentally
influenced for generations the way researchers considered
neural mechanisms contributing to the brain’s representation of sound-source location (103). The model was thereafter consolidated by data obtained from ITD-sensitive neurons in the brain stem and midbrain, revealing that several
features of the neural code matched Jeffress’ predictions
(e.g., submillisecond coincidence detection and the existence of characteristic delays). Moreover, the finding of an
almost exact manifestation of the delay-line concept in the
avian brain appeared to confirm the general validity of this
model.
However, it is fundamentally important to bear in mind
that the evolution of the mammalian auditory system occurred independently from that of birds. Consequently,
brain mechanisms responsible for processing binaural cues
developed under different evolutionary pressures, leading to
distinct constraints for sound localization mechanisms, e.g.,
different hearing ranges, and head and ear morphology. The
Jeffress-like labeled-line mechanism of ITD processing and
the related topographic representation of space (as reported
for the owl) are related to a number of specializations not
present in the mammalian system. An important aspect of
the differences between birds and mammals is that, in the
mammalian auditory system, the two binaural localization
cues are utilized in distinct frequency ranges (ITD for low
frequency, ILD for high frequency) with the analysis of monaural, spectral cues employed to resolve the cone of confusion along the vertical axis. Both spectral cues and ILD
processing show no evidence of a representation based on
labeled lines, bringing into question the necessity of such a
representation for ITDs. Finally, recent evidence concerning
mechanisms of neural tuning for ITD, including the role of
inhibition, as well as the form of the representation of ITDs
in the MSO and IC, are not well described by the Jeffress
model, but rather favors an alternative theory of binaural
sound localization first mooted by von Bekesy in the 1930s
(254) and later developed by van Bergeijk (1962, Ref. 250), in
which the neural representation of auditory space is arranged in the form of broadly hemispheric channels, with
horizontal space encoded in the form of an average populaPhysiol Rev • VOL
tion response. This is consistent with recent evidence from
ITD and ILD recordings. Indeed, the appearance of neurons
with broadly tuned response functions is characteristic of
the majority of studies examining auditory spatial tuning in
mammals and is evident across a wide range of species and
stages of brain processing from brain stem to cortex [brain
stem: gerbil (18, 181); midbrain: guinea pig (146, 215), cat
(86), gerbil (219), chinchilla (246); A1: cat (232)].
To this end, the representation of auditory space in
the mammalian brain might best be described as a relative
rate code, comparing activity across brain hemispheres
rather than within individual brain nuclei, a more distributed and therefore more plastic code compared with the
“hard-wired” local code suggested in the Jeffress model,
and evident in the avian brain.
We trust that it has become apparent to the reader
that brain mechanisms underpinning sound localization in
vertebrates are not only interesting of themselves, the
current state of the field being characterized by evolving
views and concepts, but also that they represent a general
model system by which a broader understanding of brain
processing may be obtained. First, the almost unique
structure-function relationship of the binaural system,
combined with the few physical cues involved in sound
localization, allow for very specific and testable hypotheses
of how information is processed in neuronal circuits. Second, the different implementations of binaural systems, in
particular in birds and mammals, are informative as to the
range of possible strategies of computing and coding information in the brain and how these strategies might depend
on phylogeny and evolutionary precedents of a nervous
system. Third, new insights concerning the exquisite balance of excitatory and inhibitory inputs, down to the submillisecond range, and how the recent history of activation
influences this balance, renders the auditory pathway a potential model system for studying age-related changes that
affect neurotransmission in a variety of ways.
APPENDIX A: DO HUMANS LACK THE MNTB?
Besides the logical impossibility of having to provide evidence of
absence, one must consider that the MNTB is sited within one of
the most prominent fiber bundles in the entire human brain: the
trapezoid body, with its highly myelinated fibers crossing the midline from both cochlear nuclei. Many of these fibers traverse the
MNTB itself, and hence, MNTB neurons are literally spread apart
from each other, making it difficult to delineate the nucleus by
traditional histological means. In many species, particularly those
with good low-frequency hearing, high-quality histological preparations are required to define the MNTB as a distinct structure, and in
humans, this represents a particular problem. Nevertheless, Bazwinsky et al. (9) managed to demonstrate the existence of neurons residing within the trapezoid body fibers that receive parvalbumin-positive synaptic terminals. Because MNTB inputs in other
mammals contain parvalbumin (53), it is therefore likely that the
MNTB is simply difficult to delineate in humans and that this has
led to the misunderstanding, perpetuated to this day, that it is
absent altogether. Interestingly, the first study claiming that humans do not possess an MNTB (158) described a structure the
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authors referred to as “nucleus of the trapezoid body” (NTB, in
their paper), which is sited in some distance from the location of
the MNTB. This study ignored the Nissl-stained cell bodies precisely at the position where MNTB would be in other mammals,
and where Richter et al. (199) described loosely arranged single
cells with morphological characteristics resembling MNTB neurons in other species. What Moore and Moore (158) referred to as
NTB resembles, and was most likely mistaken for, a group of
peri-olivary neurons, or possibly the ventral nucleus of the trapezoid body (VNTB). This particular region of the brain stem, in fact,
appears somewhat different in other primates, perhaps not surprising given these neuronal clusters are known to be arranged slightly
differently in almost every species (for discussions of this problem,
compare Refs. 79, 82, 209, 210). Hence, the view that the MNTB is
absent from the human brain was initiated with a publication that
was, almost certainly, referring to a different neural population.
Furthermore, Strominger and Hurwitz (236) pointed out that the
human MNTB was not easily delineated as a clear nucleus, leading
some authors to deny its existence in humans.
Together, the problematic “evidence” against the existence of
an MNTB in the human brain stem with the, admittedly weak
(for the same reasons), positive evidence for its existence, raises
conceptual problems for the existence of a prominent LSO in
humans; its absence would bring into question the evolutionary
understanding and the important general role of the MNTB, and
a strong case exists for both the existence and the importance of
this nucleus in the human brain.
APPENDIX B: ITD PROCESSING: IMPORTANT DEFINITIONS
The following are expressions frequently used in discussions
on ITD processing.
Jeffress Model
Model of ITD processing put forward by L. Jeffress (1948), based
on three crucial assumptions: 1) ITD detection via neuronal coincidence detection of binaural excitatory inputs, 2) “delay lines”
(systematically varying axonal length from both ears) adjust the
coincidence detectors to different best ITDs by compensating for
all possible ITDs, and 3) creation of a topographic representation
of ITDs in each frequency channel via evenly distributed and systematically varying tuning functions.
Labeled Line Code
Coding strategy in which each ITD is encoded by a specific
subset of neurons within the population of neurons. It follows
that the identity of each neuron is preserved in order to allow
upstream evaluation. This is a direct consequence of Jeffress
model-like ITD processing.
Peak Coding Strategy
Coding of a specific ITD via the peak activity of single or few
neurons within a heterogeneously tuned population. Typically
linked to a labeled line code, although not obligatory.
Average Population Coding Strategy
Coding of ITDs via response rate modulation along the slope
of the tuning function of a neuron. Individual neurons in a
population are tuned similarly and do not require to be identified
for upstream evaluation.
Space Map
Topographic representation of external space (azimuth and
elevation) via an ordered arrangement of systematically varying
neuronal receptive fields along multiple axes of a nucleus.
Physiol Rev • VOL
1005
Two-Channel Model
Model of ITD processing on the basis of the average population
coding strategy in which two broadly and inversely tuned channels
are created by the populations of neurons in the two brain hemispheres. The location of a sound source is encoded in the inversely
proportional relative firing rates in the two channels.
APPENDIX C: ROLE OF GLYCINERGIC INHIBITION IN ITD
PROCESSING IN THE MSO
Indirect evidence for an important role of the inhibitory inputs
to the MSO for tuning ITD sensitivity comes, on one hand, from in
vitro experiments in which contralaterally driven inhibitory inputs
were found to dominate binaurally coincident excitation (80). This
occurs only over a very short time window (a few hundreds of
microseconds) when examined in acute brain slices excised some
10 days following hearing onset (81). In fact, these inhibitory effects are extremely strong, generated by some of the fastest- and
shortest-acting inhibitory currents measured to date. When measured during blockade of other currents, which normally increases
input resistance, potentially slowing membrane kinetics, time constants of isolated glycine currents (measured in even younger
tissue; 4 –5 days following hearing onset) remain in the range of 1–2
ms (136, 221). More direct evidence for the role of inhibition in
generating internal delays comes from pharmacological studies of
the gerbil MSO in vivo, which indicate that glycinergic inhibition
plays a major role in determining the ITD sensitivity of single MSO
neurons. During blockade of glycinergic inhibition by means of
local iontophoretic application of its antagonist, strychnine, neural
discharge rates are elevated, as expected. More interesting, however, the inhibitory block asserts an asymmetric effect on ITD
functions of the neurons tested: notably, the slope of the ITD
function closest to zero (the slope “facing” ipsilateral ITDs) shifts
to beyond the physiological range due to increased responsiveness
to ipsilateral leading ITDs. As a result, the BITD shifts toward 0 ITD
(indicating less effective contralateral-leading stimulation; Fig. 14).
In contrast, the contralateral-facing slope is almost unaffected by
blockade of inhibition. These effects are reversible, with the BITD
returning to its original value a few minutes following termination
of the iontophoretic application of strychnine (18, 181). The effect
of blocking glycinergic inhibition with strychnine shifts both the
onset as well as the ongoing component of each neuron’s ITD
function.11 A likely explanation for this effect is that glycinergic
inhibition provides for a net delay in the effective contralateral
excitation. Two potential scenarios had been posited for this effect.
One assumes the action of tonic synaptic inhibition, and the other
the action of phase-locked synaptic inhibition. To differentiate
between these two possibilities, Pecka et al. (181) applied glycine
iontophoretically to MSO neurons. The rationale of this experiment
is that in the event that glycinergic inhibition is tonic, further tonic
application would enhance the contralateral delay (277), but would
mask the effect of inhibition if endogenous glycinergic inhibition is
phase-locked. BITDs should shift to even longer ITDs if the endogenous inhibition is tonic but should cause a similar shift to that
observed during inhibitory block (although at a highly reduced
discharge rate) if the timing of the inhibitory input is important.
The results favored the latter scenario: tonic glycine application
11
There was a recent debate (104) about the example cell displayed in
the original publication showing the strychnine effect (18), which was,
unfortunately for an example, heavily dominated by the onset effect. The
authors therefore raised the possibility that the observed effects reflect
mainly an “onset artifact.” A careful statistical analysis and the examples
shown in Pecka et al. (181), however, reveal that the glycine affects both
onset and ongoing component roughly equally.
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GROTHE, PECKA, AND McALPINE
FIG. 14. Shown are predicted and measured shifts of IPD tuning during iontophoretic application of strychnine and glycine application.
A: control condition. 1: Contralateral PSP (black line): the hypothesis of timed inhibition states that the contralateral IPSPcontra (light blue dashed
line) precedes the contralateral EPSP (brown dashed line) on a cycle-by-cycle basis, resulting in a delay of the contralaterally evoked net excitation
(shaded area under black line). 2: Binaural interaction (blue) of the net contralateral PSP (black) with the EPSPipsi (gray) at different IPDs. Maximal
coincidence of net excitation from both ears occurs for contralateral-leading IPDs (right-most column of panels) compensating for the inhibitoryinduced delay of the contralateral excitation. 3: Resulting IPD function: yellow-, light brown- and dark brown-filled circles correspond to the three
stimulus conditions shown in A2. B: effect of strychnine application. 1: Iontophoretic blockade of the timed inhibition with strychnine results in a
net contralateral PSP that is identical to the contralateral EPSP (brown line, compare with brown dashed line in A1). Hence, the net contralateral
PSP is advanced in time and broadened (indicated by red arrow) compared with the control condition (dashed black line). 2: Maximal binaural
coincidence during strychnine application occurs at IPDs near 0 cycles (middle column of panels). Ipsilateral-leading IPDs also create suprathreshold net binaural PSPs (left column of panels) due to partial overlap of ipsilateral- and contralateral-evoked excitation. This results in overall
increased response rates and a broadening of the IPD function on the left side of the function, shifting the peak towards 0 IPD (3). C: effect of tonic
application of glycine. 1: Tonic glycine induces a tonic hyperpolarization (black arrow and orange dotted line), with two important effects. First,
the timing of endogenously generated inhibition is masked; hence, the net PSPcontra is not delayed. Second, due to the hyperpolarized resting
potential, the effect of the synaptic excitation is reduced compared with control or strychnine condition. Compared with the control condition, this
reduction has the most pronounced impact in the declining tail of the PSP (indicated by orange arrow). 2: This results in EPSPipsi and PSPcontra to
coincide at IPDs near 0 cycles, with only a small fraction of the net binaural PSPs exceeding threshold. 3: Compared with control conditions, the right
side of the IPD function is highly reduced, resulting in a leftward shift of the overall IPD function (orange arrow). D1 and D2: these qualitative predictions
are summarized in D1 and are consistent with the recorded population data as depicted in D2 showing the average normalized spike rates of control
(n ⫽ 15), strychnine (n ⫽ 6), and glycine (n ⫽ 11) conditions (asterisks, diamonds, and closed circles, respectively). For averaging, responses were binned
in IPD widths of 0.125 cycles. Average normalized IPD functions were derived from these mean values by Gaussian fits. The R2 values of the fits were 0.92,
0.98, and 0.92 for the control (blue), strychnine (red), and glycine (orange) conditions, respectively. [From Pecka et al. (181).]
resulted in a net shift in the ITD functions in the same direction as
that observed during strychnine application. Importantly, unlike
with strychnine application, the contralateral-facing slope of ITD
functions was most affected by tonic glycine application, an outcome also predicted by the timed-inhibition scenario (Fig. 14, see
figure legend for details). In particular, this scenario relies on the
existence of phase-locked, and therefore well-timed, inhibitory inputs derived mainly from the contralateral side. Such inputs could,
with each cycle of the stimulus fine-structure, postpone the net
Physiol Rev • VOL
excitation arriving from the contralateral side if contralaterally
evoked inhibition precedes contralaterally evoked excitation by a
few hundred microseconds (18, 74). This may seem counterintuitive, since the inhibitory pathway has to pass an additional synapse
(in the MNTB) before reaching the MSO. However, the inhibitory
pathway, as described in detail above, shows numerous specific
specializations to enable fast transmission (255).
Another unexpected feature of this scenario, based as it is on
a fast-acting, phase-locking inhibition, is that the speed of inhi-
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MECHANISMS OF SOUND LOCALIZATION IN MAMMALS
bition is generally considered too slow to allow for any such
phase-locked action. Thus the question might arise, Is inhibition
fast enough? As outlined in the main body of the text, repolarization time constants for the inhibition in the gerbil MSO assessed in vitro are in the range of 1–2 ms (136) and effective in
suppressing subsequent firing for ⬍1 ms (81), which would be
sufficiently fast for the proposed mechanism of ITD processing for
frequencies up to at least 1 kHz. The question remains then, What
happens for higher frequencies? Interestingly, recent calculations
based on optimal coding theory suggested a dichotomy for ITD
coding strategies dependent on frequency with the cutoff frequency being ⬃1 kHz for the gerbil (88) (for details, see sect.
IIIC2B).
ACKNOWLEDGMENTS
Present address of D. McAlpine: UCL Ear Institute, University College, London, UK.
Address for reprint requests and other correspondence: B.
Grothe, Div. of Neurobiology, Ludwig-Maximilians-Universitaet
Munich, Grosshaderner Strasse 2, D-82152 Martinsried, Germany (e-mail: grothe@lmu.de).
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